Aug 2026· Annals of the New York Academy of Sciences· Vol 1562· 0 citations· 58 references
Medicine
TL;DR
It is suggested that restoring LKB1 activity via HDAC inhibition or miRNA targeting may represent a therapeutic avenue to address dystrophic muscle dysfunction in Duchenne muscular dystrophy.
Abstract
Efficient skeletal muscle contraction requires tight mechano‐metabolic coupling, a process regulated by AMP‐activated protein kinase (AMPK). Duchenne muscular dystrophy (DMD) is characterized by aberrant AMPK activation and disrupted metabolic signaling. This study investigates the expression and regulation of the LKB1–STRADα–MO25 heterotrimeric complex, the primary upstream activator of AMPK, in DMD models. We analyzed muscles from dystrophic mice (BL10 mdx and D2 mdx) and patient‐derived cells and found significant downregulation of the LKB1 complex across all disease stages in the DMD models, a defect not observed in an amyotrophic lateral sclerosis model. Treatment with the broad‐spectrum HDAC inhibitor vorinostat effectively restored LKB1 expression at both transcript and protein levels in D2 mdx mice. This restoration was mechanistically linked to downregulation of miR‐451, miR‐195, and miR‐17, which function as post‐transcriptional repressors of LKB1. Conversely, the selective HDAC1/2 inhibitor Rodin‐A increased Lkb1 mRNA but failed to rescue protein levels or alter miRNA expression. Our data identify the axis LKB1–STRADα–MO25 as a critical regulatory node that is disrupted in DMD, but remains responsive to epigenetic modulation. These findings suggest that restoring LKB1 activity via HDAC inhibition or miRNA targeting may represent a therapeutic avenue to address dystrophic muscle dysfunction.
It is demonstrated that TMZ mitigates dystrophic pathology by targeting the ATP6AP2 signaling axis and dampening macrophage-mediated inflammatory responses, highlighting its potential as a novel immunopharmacological therapeutic strategy for DMD.
Lin Zhou, Yu Zhang, Xinxin Tan et al.· International Immunopharmaco...· 0 citations
ABSTRACT Chronic glucocorticoid (GC) exposure is the leading clinical cause of skeletal muscle atrophy, steroid myopathy, and secondary sarcopenia, triggering irreversible motor function decline, disease progression, and elevated all‐cause mortality. The underlying pathological mechanisms remain unclear, and no safe and effective targeted interventions are currently available. This study identifies Lipocalin 2 (LCN2) as a pivotal driver of GC‐induced muscle atrophy. Using multi‐omics analysis, dexamethasone‐induced mouse models, primary myotube models, and gain/loss‐of‐function assays, we found that LCN2 was the most strikingly upregulated factor in atrophic muscle, and that its transcription was directly activated by glucocorticoid receptor (GR) binding to the conserved glucocorticoid response element (GRE) in its promoter. Muscle‐specific LCN2 overexpression disrupts extracellular matrix (ECM) homeostasis and triggers severe muscle atrophy and motor dysfunction, whereas LCN2 silencing markedly alleviates GC‐induced ECM injury and atrophy without impairing normal muscle homeostasis. Mechanistically, the interaction of LCN2 with matrix metalloproteinase 9 (MMP9) triggers ECM dysregulation and consequent focal adhesion kinase (FAK) signaling inactivation, which represses the PI3K‐Akt‐mTOR anabolic cascade and activates FoxO‐driven catabolic signaling, thereby leading to dysregulated muscle protein metabolism. This study reveals the core pathogenic role of the LCN2‐MMP9‐ECM‐FAK axis in GC‐induced muscle atrophy, providing a promising novel therapeutic target for steroid myopathy.
Hongwei Shi, Xiaojing Hao, Yi Yan et al.· Advancement of science· 0 citations
Results indicate that sustained AMPK activation with BMC-25 confers multifaceted benefits to DM1 skeletal muscle by improving core DM1 pathogenic features in a sex-dependent manner, and highlights the potential of natural compounds like BMCs as novel, promising and accessible therapeutics for the DM1 muscle pathology.
Shatha A. Atieh, Chimène Fahmi, Jia Liu et al.· Neurotherapeutics· 0 citations
Duchenne muscular dystrophy is initiated by dystrophin loss but is accompanied by profound metabolic remodelling. Here, we identify suppression of the muscle-enriched adenylosuccinate synthase, ADSS1, and the purine nucleotide cycle in mdx muscle. Integrated multi-omic profiling revealed a compensated purine-stress state in which nucleotide salvage and quality control were increased to preserve adenine nucleotide abundance and buffer consequential toxic/disruptive deoxy-/nucleotide production. Purine metabolism was the highest-impact joint pathway with metabolite and transcript hits in mdx muscle, and its maintenance program was directionally conserved in human ADSS1 myopathy. Interventions positioned around ADSS1 separated the outputs of this node. Ribose and dimethyl fumarate remodelled upstream or downstream stress programs, whereas only adenylosuccinic acid bypassed ADSS1 to expand the adenine nucleotide pool and remodel CoA/acetyl-CoA metabolism. All three interventions suppressed pro-adipogenic transcription without broadly correcting the lipidome. These findings identify ADSS1 as a regulated metabolic control node that couples purine retention to inflammatory and adipogenic remodelling in dystrophic muscle.
E. Rybalka, Stephanie Kourakis, Bo Qi et al.· bioRxiv· 0 citations
A variant-specific insight is revealed into CMT2A disease mechanisms and HDAC6 is confirmed as a promising target for further therapeutic development by showing that mitochondrial trafficking defects could be alleviated by treatment with an HDAC6 inhibitor.
Lydia H. Jestice, Larissa Butler, Rebecca A. Lea et al.· JCI Insight· 0 citations
Combination therapies targeting multiple of these glucose signaling pathway proteins, together with glucose and N-acetylcysteine, yielded superior therapeutic benefit in complex I disease cell and C. elegans models.
Kelsey Keith, Min Peng, Cristina Remes et al.· bioRxiv· 0 citations
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